MDMA ('ecstasy') enhances basal acetylcholine release in brain slices of the rat striatum

The pharmacological basis of acute (+/-)-MDMA (3,4-methylenedioxymethamphet amine) intoxication still awaits full characterization. According to presen t knowledge, MDMA enhances the release of serotonin and dopamine in striata l slices and interacts with different types of receptors such as 5-HT2 (5-h ydroxytryptamine or serotonin), M-1 and Ma muscarinic acetylcholine (ACh), and histamine H-1 receptors. Currently, no information is available about t he influence of (+/-)-MDMA on striatal cholinergic neurotransmission. In th e present study. we used the in vitro perfusion technique to investigate th e effect of (+/-)-MDMA on ACh release in rat striatal slices. Perfusions wi th (+/-)-MDMA (10-300 mu M) resulted in a dose-dependent increase of sponta neous ACh release (EC50 approximate to 30 mu M). The effect was reversible and Ca++- and tetrodotoxin-sensitive. To determine the neurochemical pathwa ys underlying this response, we perfused with (+/-)-MDMA in the presence of various inhibitors of neurotransmitter receptors, Blockade of glutamate or muscarinic ACh receptors as well as 5-HT1, 5-HT2, 5-HT3C or dopamine D-2 r eceptors did not modulate (+/-)-MDMA-induced ACh release. However, the pres ence of histamine H1 receptor antagonists in the perfusion medium abolished (+/-)-MDMA-induced ACh release. The present data clearly demonstrate that (+/-)-MDMA enhances the activity of striatal cholinergic neurons and sugges t an involvement of histamine H1 receptors. The effect is not mediated by g lutamate and does not involve the activation of receptors of dopamine Dg, 5 -HT1, 5-HT2, 5-HT3C or muscarinic ACh. Considering the relatively high affi nity of (+/-)-MDMA for the H-1 histamine receptor (Ki 6 mu M), a direct act ivation of this type of receptor might represent a plausible mechanism for (+/-)-MDMA-induced ACh release.